Abstract 2430: The role of SOX2 in Barrett's esophagus development
Authors: Ramon U. Jin, Toni M. Nittolo, Jean S. Wang, Jason C. Mills, Qing K. Li
Journal: Cancer Research (2023)

Abstract Background: Barrett’s esophagus (BE) is a precancerous condition defined as replacement of the normal esophageal squamous epithelium with metaplastic columnar intestinal epithelium caused by chronic gastroesophageal reflux disease. Importantly, BE confers the strongest predisposition to developing esophageal adenocarcinoma. There is a deficiency of knowledge regarding the molecular pathogenesis of BE development. To this end, a thorough elucidation of the development context by which BE develops will uncover novel avenues to detect BE and revert it back to normal esophagus to ultimately halt the development of cancer. Spatial specification of the developing digestive tract occurs through a series of regulated transcriptional cascades. At embryonic day 9, the dorsal foregut is marked by expression of SOX2, a transcription factor of the Sry-like HMG box family, which is required for esophageal development. SOX2 continues to be expressed in the esophageal epithelium throughout adulthood as an important homeostatic maintenance factor. I hypothesize that SOX2 functions to maintain foregut squamous epithelial identity, and its loss is a critical step during BE development. Methods/Results: Here, we show using human BE tissue microarrays that SOX2 is expressed in the normal squamous epithelium and its expression is significantly decreased during BE development. To assay the molecular effects of SOX2 expression changes, we have conducted a series of novel complementary experiments involving a foregut-specific inducible Sox2 knockout mouse model and a biobank of human BE derived organoids. Using the murine model, Krt5CreER/+; Sox2flox/flox; ROSA26LSLTdTomato/+, we have assessed the histologic and transcriptional effects of SOX2 loss on squamous epithelium homeostasis. In addition, we have conducted a series of experiments involving a wholly novel biobank of human Barrett’s esophagus derived organoids. We have been able to expand, cryopreserve, and genetically manipulate these primary cells, and here we characterize these organoids and show that they recapitulate key pathohistologic and molecular features of BE. Using the human BE organoid biobank, we have established BE organoids that have forced expression of SOX2, and we are developing a high-throughput screening system using a SOX2 luciferase promoter reporter assay to identify novel compounds and drugs that induce SOX2 expression. Immediate future avenues will involve defining the direct transcriptional targets of SOX2, and interactions with the intestinal transcription factor CDX2. Conclusions: In summary, it is possible that in BE there is a stepwise transcriptional progression towards a more posterior phenotype with loss of SOX2 expression being an important initial step. Together, these experiments will elucidate novel molecular pathways involved in BE maintenance and may reveal novel therapeutic avenues to treat BE and prevent esophageal cancer. Citation Format: Ramon U. Jin, Toni M. Nittolo, Jean S. Wang, Jason C. Mills, Qing K. Li. The role of SOX2 in Barrett's esophagus development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2430.